Novel cellular oncogenes and tumor suppressor genes (TSG), which would fit the classic criteria of a cancer gene associated with already recognized chromosome hot spots (such as the loci of recurrent gains at 20q13 and of LOH at 16q22), remain elusive. Therefore, most recent advances in cancer research include re-thinking of the genetic two-hits model to emphasize epigenetic mechanisms - aberrant methylation of regulatory regions, loss of imprinting (LOI) at IGF2/H19 and other loci, and/or heterogeneity in epigenetic reprogramming/maintenance. The most recent results obtained in the Molecular Pathology Section suggest that each of these seemingly unrelated cancer events, plus one of the other most frequently observed features of cancer - deregulated expression of MYC, - might be causally linked to the unique pair of paralogous genes mapped on chromosomes 16q22 and 20q13. Both genes have been discovered by scientists lead by the Head of MPS LIP NIAID, Dr. Victor Lobanenkov, and both were patented for a wide range of applications in basic and clinical medicine. One gene was named CTCF (for CCTC-binding factor), and the other BORIS (for Brother of the Regulator of Imprinted Sites, referring to the role of CTCF in reading of gene imprinting marks). Two siblings are equipped with the identical 11 Zn-finger (ZF) domain to interact with the same spectrum of CTCF/BORIS-binding sites, but diverge at the amino- and carboxy-termini. Normally, only CTCF but not BORIS is expressed in all somatic cells. During male germ cell differentiation, the pair displays mutually exclusive expression pattern that correlates with the patterns for (1) genome-wide re-establishing of DNA-methylation marks and (2) certain testis-specific chromatin-remodeling factors, and DNMTs. While CTCF has properties of a candidate TSG at 16q22, abnormally activated BORIS is oncogenic, and found to be expressed in many malignancies with gains or amplifications at 20q13. Novel data obtained by MPS and collaborators with several types of such cancers lead to following major conclusions: (i) BORIS is a new member of the so-called cancer/testis (CT) gene family with a great promise for cancer diagnostic and therapy applications; and (ii) the most common mechanism to deregulate TSG function of CTCF on one chromosome may result from the abnormal activation of BORIS on another. Both published and ongoing studies illustrate contributions of CTCF/BORIS-pair in epigenetic gene regulation and cell proliferation control by describing in details the two sets of distinct CTCF-binding sites characterized in IGF2/H19 and in MYC loci. These studies show that -combinatorial mode- and -in vivo accessibility- to be the main key words to understanding of functional consequences resulting from in vivo interactions of CTCF and BORIS with unusually diverged and long target DNA sequences.